1. Field of the Invention
The present invention relates to methods and reagents for promoting smoking cessation. The present invention relates to methods and reagents for preventing smoking addiction. The present invention also relates to methods and reagents for treating nicotine addiction.
2. Background of the Invention
Smoking addiction is a complex phenomenon believed to involve cognition enhancement, psychological conditioning, stress adaptation, reinforcing properties and relief from withdrawal. Consequently, providing therapeutic treatment for smoking addiction is an extremely difficult challenge.
Tobacco products, including cigarettes, cigars, pipes and smokeless tobacco, can cause a variety of well-recognized health problems. From a public health perspective, it is desirable to stop consuming tobacco products, especially in the form of smoking. However, some individuals cannot quit smoking tobacco products, in spite of focused attempts to succeed. One major factor in the difficulty of quitting smoking is the presence of nicotine in tobacco.
Nicotine can produce a myriad of behavioral effects and is unquestionably one of the most popular and powerful reinforcing agents. In addition, smoking, arguably the vehicle of choice for nicotine delivery, may cause a variety of well-recognized health problems. For these reasons it has sometimes been desirable to cease consumption of nicotine. However, for some, the termination of nicotine consumption can not be accomplished, in spite of focused attempts to succeed.
One method for assisting smoking cessation is to reduce consumption over time. For complex reasons, this method is not always entirely successful. One method for assisting smoking cessation is to provide an alternate delivery vehicle for nictone. Such delivery vehicles include oral preparations such as gums, and transdermal vehicles such as skin patches.
Another method for assisting smoking cessation is to replace the nicotine signal from tobacco with a substitute reinforcer. Bupropion is used to promote smoking cessation and it may act as a substitute reinforcer.
Nicotine antagonists have been considered as an approach to smoking cessation. A nicotine antagonist would block the reinforcing signal from nicotine that creates and maintains the addiction to smoking. Over time, the smoker would dissociate the physical and psychological aspects of smoking. For example, mecamylamine has been used to promote smoking cessation, although it is generally ineffective alone. Another approach is to administer an antagonist, e.g., mecamylamine, together with nicotine replacement therapy. Compounds which act as nicotine substitutes and block nicotine""s effects would be preferred smoking cessation reagents.
Lerner-Mamarosh et al. Life Sci. 56:67-70 (1995) describe antagonism of nicotine""s action by 3-phenyl-substituted tropane analogs of cocaine. The study demonstrated that the phenyltropanes blocked nicotine-induced seizures in mice. The authors also found that the analogs could compete with mecamylamine, an indirect nicotine antagonist, in vitro. However, the results of this study do not suggest that the phenyltropane compounds could be used to treat nicotine addiction and provide a method of smoking cessation.
The phenyltropane analogs were well-known to inhibit the reuptake of dopamine, serotonin and norepinephrine. Lerner-Mamarosh et al. demonstrated that the anti-seizure activity of the phenyltropanes correlated with the ability of the analogs to inhibit the dopamine transporter. Therefore, it was highly likely that the anti-seizure activity was an indirect effect of the phenyltropanes on dopamine.
Lerner-Mamarosh et al. also found that the analogs could compete with mecamylamine, an indirect nicotine antagonist, in vitro. Therefore, the authors speculated that the anti-seizure activity could be due to the interaction of the phenyltropanes with a nicotinic acetylcholine receptor. Even if this speculation were true, this finding would not suggest that the phenyltropane compounds would be useful for smoking cessation. There are a large number (at least 1000) of different nicotinic acetylcholine receptors (nAChRs). The nAChRs are composed of various alpha(2-9) and beta(1-4) subunit combinations. Even now very little is known concerning the specific receptor involved in any particular pharmacological response. Some data suggest that nicotine-induced seizures appear to be mediated by the alpha-7 nicotinic receptors. Other data suggest that this class of receptors does not mediate nicotine reinforcement. Nicotine reinforcement is central to nicotine addiction. Therefore, these experiments do not suggest that these compounds would block nicotine and be useful smoking cessation reagents.
In spite of the known methods for treating smoking addiction, there remains a lack of generally effective means of treating and/or preventing smoking addiction. Accordingly, there remains a strong need for methods of treating smoking addiction.
It is an object of the present invention to provide methods and reagents for smoking cessation.
It is another object of the present invention to provide methods and reagents for treating nicotine addiction.
It is another object of the present invention to provide methods and reagents for preventing smoking addiction.
The objects of the invention, and others, are accomplished with a method of training a smoker to quit smoking, comprising administering to a smoker in need thereof an effective amount of a tropane compound represented by the formula: 
wherein
R1 is CO2R3, CONR4R5, R6, CH2R6, 
R3 is H, C1-6alkyl, C3-8cycloalkyl or 
R4 and R5 are each independently, H, C1-6alkyl, C2-6alkene, C2-6alkyne, CH2-COxe2x80x94phenyl, phenyl, phenyl substituted with 1-3 of C1-6 alkyl, C2-6alkene, C2-6alkyne or C1-6 alkoxy, hydroxy, CH2OH, C1-6alkoxy, phenoxy, amino, amino substituted with 1 or 2 C1-6 alkyl, C2-6alkene, C2-6alkyne, C1-6alkoxy, C1-8acyl, phenyl, or phenoxy, or R4 and R5 may combine to form, together with the nitrogen atom to which they are bonded, a cyclic structure selected from the group consisting of a pyrrolidinyl group, morpholinyl group, piperidinyl group and a group represented by the formula 
R6 is OH, H, C1-6alkyl, C3-8cycloalkyl, C1-6alkoxy, Cl, Br, I, CN, NH2, NHC1-6alkyl, N(C1-6alkyl)2, OCOxe2x80x94C1-6alkyl, OCOxe2x80x94C1-3alkylaryl, CO2xe2x80x94C1-6alkyl, CO2xe2x80x94C1-3alkylaryl or substituted phenoxy;
R7 is H, C1-6alkyl, C3-8cycloalkyl, C1-6alkoxy, C2-6alkynyl, halogen, amino or; 
A is S, O or NH;
R2 is H, C1-5alkyl, halogenated C1-6alkyl, C2-6alkenyl or (CH2)nCO2Rx where n is integer of 1 to 8 and Rx is C1-6alkyl;
each X is, independently, H, C1-6alkyl, C3-8cycloalkyl, C1-6alkoxy, C2-6alkynyl, phenyl, C1-6-phenyl, halogen, amino, or acylamido, CRzxe2x95x90CRzRz, CRzRzxe2x80x94CHxe2x95x90CRzRz, Cxe2x95x90xe2x80x94CRz, C(xe2x95x90RzRz)Rz;
each Rz is, independently, H, C1-6alkyl, phenyl, substituted phenyl, CH2OH, C1-6-phenyl;
each Y is, independently, H, I, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2NH2, CO2R8, C1-6alkyl, NR9R10, NHCOR11 or NHCO2R12;
R8 is H or C1-6alkyl; and
R9, R10 R11 and R12 are each, independently, H or C1-6alkyl,
or X and Y, taken together with the phenyl group to which they are bonded, form a 2-naphthyl group,
the dotted line between C2 and C3 represents a single or double bond,
or a pharmaceutically acceptable salt thereof.